|Year : 2016 | Volume
| Issue : 1 | Page : 96-101
Optimizing treatment and analysis of prognostic factors for locally advanced nonsmall cell lung cancer in resource-limited population
JP Agarwal1, C Hotwani1, K Prabhash2, A Munshi1, S Misra1, A Mathew1, N Kalyani1, V Noronha2, SG Laskar2, A Joshi2, N Purandare3, S Tandon4, V Sharma2
1 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Pulmonary Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||28-Apr-2016|
J P Agarwal
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Lung cancer most commonly presents in advanced stages in developing countries, where combined modality treatment using chemo-radiotherapy (CTRT) is the standard of care. Materials and Methods: A retrospective audit of patients of nonsmall cell lung cancer (NSCLC) treated at a single Institute from January 2008 to December 2012 was conducted. Various prognostic factors affecting disease-free survival (DFS) and overall survival (OS) were studied by univariate and multivariate analysis. All patients were meticulously followed-up clinically and telephonic contacts. Results: Overall 171 patients of NSCLC were treated with definitive CTRT using concurrent chemotherapy in 66% patients and sequential therapy in 28% patients. The actuarial 2 years DFS was 17.5% and 2 years OS was 61.5%. Complete response to treatment resulted in significantly better DFS and OS. Definitive CTRT was very well-tolerated in these patients with good compliance. Conclusion: Definitive CTRT, sequence being individualized depending on performance status and disease stage at presentation, is a feasible and effective treatment modality for locally advanced NSCLC patients in the developing world. Response to treatment is an important prognostic factor for treatment outcomes.
Keywords: Chemo-radiotherapy, nonsmall cell lung cancer, prognostic factors, response
|How to cite this article:|
Agarwal J P, Hotwani C, Prabhash K, Munshi A, Misra S, Mathew A, Kalyani N, Noronha V, Laskar S G, Joshi A, Purandare N, Tandon S, Sharma V. Optimizing treatment and analysis of prognostic factors for locally advanced nonsmall cell lung cancer in resource-limited population. Indian J Cancer 2016;53:96-101
|How to cite this URL:|
Agarwal J P, Hotwani C, Prabhash K, Munshi A, Misra S, Mathew A, Kalyani N, Noronha V, Laskar S G, Joshi A, Purandare N, Tandon S, Sharma V. Optimizing treatment and analysis of prognostic factors for locally advanced nonsmall cell lung cancer in resource-limited population. Indian J Cancer [serial online] 2016 [cited 2019 Nov 13];53:96-101. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/96/180810
| » Introduction|| |
Lung cancer is the most common cancer world-wide, with 1.8 million cases being diagnosed every year globally and is one of the leading causes of death. In India, 63,000 new cases are diagnosed every year, with approximately 35% of them being locally advanced at presentation. In selected group of patients with unresectable lung cancer, radiotherapy combined with chemotherapy remains the standard of care., However, there is an ongoing debate over selecting the optimal schedule and sequence of chemotherapy. In the nonsmall cell lung cancer (NSCLC) collaborative group meta-analysis, the hazard ratio (HR) for sequential chemotherapy was 0.88 whereas that for concurrent chemotherapy, the HR was 0.89. Furthermore in the meta-analysis by Aupérin < et al., there was an overall survival (OS) benefit with concurrent chemotherapy.
This study reports an audit of consecutively treated patients of locally advanced NSCLC with curative intent using systemic therapy in the form of sequential or concurrent chemotherapy along with radiotherapy, in resource constrained settings with a view to compare outcomes with those reported from the developed world.
| » Materials and Methods|| |
Histologically proven unresectable or medically inoperable NSCLC patients, treated with curative intent using combination strategies of radiotherapy and chemotherapy during January 2008 through December 2012 at a tertiary cancer center form the subjects of this audit.
Patients were positioned supine using thoracic arm rest with arms overhead, chin to supra-sternal notch distance was measured for reproducibility. Fiducials were placed at the level of the nipple in males and at 4–5th intercostal space in females and intravenous contrast was injected at 2 ml/kg after confirming normal renal function. A total of 5 mm thick computed tomography (CT) images were acquired from chin to L-2 vertebra. Baseline F-18 fluorodeoxyglucose positron emission tomography (FDG PET)-CT was performed for staging and for target delineation using visual assessment method. Isotropic clinical target volume margin of 7 mm respecting normal barriers of presumed spread with editing and planning target volume (PTV) margin of 1 cm was given. Three-dimensional conformal radiotherapy plans were generated on eclipse treatment planning system version 8.6 (Varian Medical System, Palo Alto USA) treatment planning system using coplanar or noncoplanar beam arrangement with appropriate energy (6/15 MV) photons.
Demographic details recorded included patient factors-age, gender, presenting symptoms, habits, comorbidities and Karnofsky performance status (KPS); tumor-related factors–stage and histology and treatment-related factors–sequence of chemotherapy in relation to radiotherapy, chemotherapeutic agents used, dose of radiotherapy. Target volumes (gross tumor volume [GTV] and PTV) and organ at risk volumes (lung-PTV) were recorded and correlated with outcomes.
Patients were evaluated for response at 2 months after completion of chemo-radiotherapy (CTRT) with similar baseline imaging modality. Response to treatment was defined as per World Health Organization criteria as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Subsequently patients were meticulously followed-up regularly with clinical examination and investigations, which were tailored as per patients' symptoms. In case of nonpresentation on the due date, the patients were telephonically called up to find out their status.
Disease-free survival (DFS) was defined as the period from the confirmation of diagnosis and staging to the date of recurrence/progression of disease either loco-regionally or distally in those with CR or any residual disease in partial responders to definitive therapy. OS was defined similarly until the death of the patient due to any cause. DFS and OS curves were generated using Kaplan–Meier method.
Patients receiving induction or adjuvant chemotherapy with or without concurrent chemotherapy were combined as sequential group while patients receiving only concurrent chemo formed concurrent group for subgroup analysis.
To assess the influence of prognostic factors on survival, various patient, tumor and treatment-related factors in univariate and multivariate analysis using log-rank test cox-regression model respectively was performed. Patients lost to follow-up were censored when last seen both for DFS and OS.
| » Results|| |
Consecutively treated 171 patients of locally advanced NSCLC with definitive intent using CTRT during this period were analyzed. Of these, 151 (88.3%) were males with a median age of 58 years (range 30–84 years). The demographic details are shown in [Table 1]. Patients had median KPS 80 (range 60–100) with 45% patients having comorbidities.
Median GTV and PTV volumes were 132 cc (16.7–741 cc) and 538 cc (56–5680 cc) respectively. The median lung-PTV volume was 2599 cc (1023–6448 cc), and V-20 Gy was 24.01% (6.8–49.0%). All patients received thoracic external beam radiotherapy to a median dose of 60 Gy (range 04–66 Gy) over a median duration of 44 days (range 2–85 days). Overall, 86.5% patients received chemotherapy, either concurrent given weekly or 3 weekly regimen of sequential chemotherapy, of which platinum-based doublets were used in 92% of the patients [Table 1].
Patients' compliance to concurrent CTRT was good, as 95.3% patients completed treatment without any gap and acceptable toxicity. However, two patients died while on treatment, whereas three patients defaulted.
Acute pneumonitis radiation therapy oncology group (RTOG) Grade II was seen in 6.4% patients whereas RTOG Grade II and Grade III esophagitis was seen in 32.2% and 4.1% respectively. Chemotherapy, either concurrent or sequential, was well-tolerated, with Grade II or more hematological and renal toxicity seen in 23.5% and 07.4%, respectively. On subset analysis, chemotherapy-related Grade II hematological toxicity was seen in 27% in sequential group and 36% in concurrent group whereas Grade II renal toxicity was seen in 11% and 4% respectively, which was not statistically significant. There was a weak correlation between GTV > 132 cc and lung-PTV volume with acute pneumonitis and esophagitis, although it may be because the toxicity data was available for only 70% patients.
For the entire cohort, at a median follow-up of 13 months (inter-quartile range 14 months, range 0–54 months), 66 (36.2%) had CR whereas 84 (49.1%) had PR or SD, 08 (4.7%) patients were lost to follow-up and 17 patients had disease progression at first follow-up. At least 86 patients had a follow-up of >1 year.
The median DFS was 7 months, and OS was 13 months. The estimated 2 years DFS was 17.5%, and 2 years OS was 61.5% [Figure 1]a and [Figure 1]b.
|Figure 1: (a) Kaplan–Meier graph showing disease-free survival in months (b) Kaplan–Meier graph showing overall survival in months|
Click here to view
Overall, 29.8% (n = 51) patients had a recurrence, of which 41% were local, 25% regional and 51% had distant metastases. Most common sites of distant metastases were bone (35%), adrenal gland (23%) and brain (11.5%).
The median DFS stratified by response was 30 months in complete responders, 6 months in those having PR or SD and 5 months in those with PD, which was strikingly significant (P < 0.001) [Figure 2]a.
|Figure 2: (a) Kaplan–Meier graph showing disease-free survival in months according to response (b) Kaplan–Meier graphs showing overall survival stratified according to response to treatment|
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Disease-free survival in nonsmokers, GTV ≤132 cc (median GTV 132 cc), PTV ≤538 cc and those receiving sequential chemotherapy showed a trend toward significance. Other patient, tumor and treatment-related factors did not show a statistically significant impact on DFS [Table 2].
For OS at 2 years, on univariate analysis, statistically significant benefit was seen in nonsmokers (median OS 52 months vs. 26 months < P = 0.028). Median survival time in advanced tumors that is, T3–T4 was 30 months, whereas the same was not attained in patients with T1–T2 tumors, 2 years survival rates between 89.1% and 55.3% respectively, which was significant [P = 0.005, [Table 2]. Other factors leading to significantly better OS on univariate analysis were complete responders to treatment and GTV ≤132 cc. The median OS was not reached in complete responders [Table 2] and [Figure 2]b.
We had combined patients receiving any form of sequential therapy along with concurrent CTRT into concurrent group whereas those receiving neo-adjuvant chemotherapy (NACT), and radiotherapy were in a sequential group. With this grouping, the 2 years DFS for concurrent group was 18.8% and for sequential group 29.8% (P = 0.089); the 2 years OS was 61.5% and 68.8% respectively (P = 0.898). Patients receiving radiotherapy alone as they were unfit for CTRT (23 patients), had 2 years DFS and OS of 6.5% and 34.0%, respectively [Table 2].
However, on separately analyzing patients receiving concurrent along with sequential chemotherapy from those receiving only concurrent CTRT, the 2 years DFS was 17% and 19.8% respectively (P = 0.123). Similarly, the 2 years OS in these was 61.5% and 62.0%, respectively [P = 0.963, [Table 2].
On multivariate modeling for various above mentioned prognostic factors, nonsmokers (P = 0.028) and CR to treatment (P = 0.000) retained statistical significance on DFS as well as OS [Table 3].
|Table 3: Multivariate analysis for prognostic factors affecting DFS and OS|
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| » Discussion|| |
Lung cancer, being most common malignancy, is also the most common cause of cancer-related mortality world-wide. In developing countries like India, more than 60% patients present in advanced or metastatic stage. This is attributed to lack of awareness, delay in diagnosis and referral (mostly being confused with tuberculosis by the primary physician), and limited accessibility to specialized centers dealing with cancer care.
Concurrent chemo-radiation is at present the treatment of choice for patients with locally advanced NSCLC as it has shown a survival benefit in various randomized trials over radiotherapy alone., However, due to its higher toxicity, this combination is mostly restricted to patients with good general condition, minimal comorbidity and who are relatively young. In a population-based study by De Ruysscher < et al., 41% patients with Stage III NSCLC were not eligible for concurrent chemo-radiation due to age and comorbidity at diagnosis. One-fourth were ≥75 years, of the younger group, only 53% had no comorbidity. Comorbidity was as expected comprising mainly chronic obstructive pulmonary disease (COPD) and cardiovascular disorders.
This audit consists of patients who were deemed suitable or borderline suitable for chemo-radiation strategies based on performance status, comorbidity, etc., It is interesting to see 57% patients did have significant comorbidity unlike the population-based study by De Ruysscher < et al., in the form of diabetes and hypertension, usually not an exclusion for chemo-radiation strategies. The reasons are patient with very poorly controlled COPDs were excluded, underestimation of overall COPD and diabetes and hypertension are the more common comorbidities in this part of the world.
Various other factors too have a prognostic impact on the treatment outcome. Patient-related factors such as age, female gender, good performance status, weight loss <5%, nonsmokers have a favorable outcome in patients treated with CTRT.,,, These factors are also important for better tolerance of CTRT. In the current audit, patients ≤58 years, females, KPS >80 and nonsmokers had favorable DFS and OS, although not statistically significant except for nonsmokers having significantly better 2 years OS (72.3% vs. 48.0%, < P = 0.028).
Among tumor-related factors, primary size, nodal involvement, and histology have been reported to have prognostic significance.,, GTV, which represents primary size, has been proven to be inversely correlated with survival, including surgical series. However, in patients being treated with radical radiotherapy, it is much more significant as local control of larger tumor requires a higher dose, due to the higher number of clonogenic cells. Recently published study by International Association for the Study of Lung Cancer, as per tumor size, the survival is statistically significantly better for T1 and worse with T3. However, the difference in survival between T3 and T2 was not statistically significant, the probable reason for which include the difference in nodal involvement and possibly presence of comorbidities though the statistical significance was weak with CTRT than primary surgery. In the current study, smaller GTV (≤132 cc) and early tumor stage had significantly better outcomes in terms of DFS and OS.
Other newer biomarkers have been recently been reported by Berghmans < et al. to affect the treatment outcome, although further studies are required to validate their common use as prognostic factors for patients of NSCLC. These include serum lactate dehydrogenase levels at presentation, carcinoembryonic antigen level, serum calcium level and apoptosis-related biomarkers such as B-cell lymphoma 2 (bcl-2), p53, apoptotic index, mutations in tumor tissue like epidermal growth factor receptor, K-ras, vascular endothelial growth factor receptors, thyroid transcription factor-1, absolute standardized uptake values of tumor tissue on FDG-PET imaging, etc., Landejik < et al. and Hwang < et al. have independently reported favorable impact of bcl-2 and high apoptotic index on progression-free survival in patients of Stage III NSCLC treated with radiotherapy.
Combining chemotherapy with radiotherapy with conventional as well as hyperfractionation has shown significant improvement on outcomes in terms of both progression-free survival and OS in various randomized studies.,, In a recent meta-analysis by Aupérin < et al., concurrent chemotherapy has shown a survival benefit over sequential chemotherapy, with a HR of 0.84 for concurrent chemotherapy. Concurrent chemotherapy led to the absolute benefit of 5.7% at 3 years and 4.5% at 5 years in OS. There was an absolute benefit in progression-free survival of 2.9% at 3 years and 2.2% at 5 years, which was mainly due to improvement in loco-regional control, which was better with concurrent chemotherapy (HR = 0.77, < P = 0.01). There was no significant difference in the incidence of distant metastases (HR = 1.04). The benefit of concurrent chemotherapy on OS could be explained by early destruction of the maximum number of neoplastic cells by combined therapy, which was not being achieved by sequential schedule to radiotherapy and chemotherapy. This improvement in outcomes however has been associated with an increase in the incidence of acute hematological as well as esophageal toxicities.
Similarly, in the present audit, the cohort of patients receiving radiotherapy alone had poor DFS and OS (6.5% and 34%, respectively) when compared to those receiving CTRT. The difference was however not statistically significant, probably because of the smaller number of patients receiving radiotherapy alone (13.4%). Most common reasons for treating patients with radiotherapy alone included advanced age, poor performance leading to tolerance of combined therapy unlikely.
Concurrent CTRT is a standard of care, and the majority of patients could be offered this treatment. However, we need to individualize the patient and tumor factors and tailor the treatment accordingly like chemotherapy followed by radiotherapy with/without chemotherapy. In the literature reported so far, the feasibility of concurrent CTRT has been reported to range around 50%, whereas the rest of 50% have been excluded from such approach due to comorbidities or age-related poor tolerance to multi-modality treatment. In developing countries like India, patients are nutritionally compromised with poor support systems, which makes the applicability of the concurrent strategies even more difficult. A second important fact that needs consideration is the patients presenting to clinics have larger volumes, leading to larger radiation portals and the dosimetric constraints for irradiated lung volume (e.g. the mean lung dose or the volume of the lungs receiving >20 Gy, i.e. the V-20) are not achievable. One of the most important reasons for giving induction chemotherapy was to reduce the volume of atelectasis/consolidation and better define the true tumor, reduce the volume of lung receiving RT therefore; improve lung function and improve compliance–something that will not be seen with concurrent or adjuvant approaches.
For the above-mentioned reasons, sequential chemotherapy and high-dose radiotherapy may be suboptimal, but still valuable alternative for patients who are not eligible for concurrent strategies. As our audit indicates, the majority of patients received concurrent chemotherapy radiotherapy (56%), and this treatment strategy was well-tolerated both in terms of toxicity and compliance.
Another subgroup of patients received sequential treatment either NACT followed by concurrent (14%), NACT followed by RT (9%) or concurrent followed by adjuvant (5.5%). Patients receiving concurrent CTRT (56%) were grouped together as concurrent while those receiving sequential (NACT/adjuvant) were grouped as sequential (30%). The reason for sequential treatment was as aforementioned. On analyzing these subgroups, patients with sequential chemotherapy had better DFS with a trend toward statistical significance as compared to concurrent chemotherapy, similar to that reported by cancer and leukemia group B 8331 study. This should be interpreted cautiously as only ⅓ patients (30.4%) received sequential chemotherapy. Also, patients having a response to induction chemotherapy (responders) were treated further with definitive radiotherapy, thus resulting in natural selection of favorable disease while those progressing on induction were excluded. This could be one of the probable explanation for better outcomes. Furthermore, on subgroup analysis, patients receiving only NACT followed by radiotherapy and receiving NACT/adjuvant along with concurrent CTRT, DFS and OS were almost similar (19.8% vs. 17% and 58.6% vs. 52.6% respectively).
Study by Vokes < et al. showed that induction followed by concurrent CTRT was not inferior to CTRT. However, in this study, treatment with concurrent CTRT was not decided based on response to induction chemotherapy, so that benefit in selective responders was not evident. In our study, overall the patients with sequential therapy fared well in terms of DFS but concurrent along with NACT had no advantage over NACT followed by RT.
Complete response to treatment leads to a statistically significant 2 years DFS as well as OS. On subset analysis, there was a strong correlation between sequence of chemotherapy and response to treatment (P = 0.910). However, this could be due to the smaller number of patients in sequential chemo-radiation group (n = 18).
Evidence-based guidelines generated from the developed world may not be generalized to resource constrained environments and need to be tailored according to local needs depending upon resources and patient population that present to the clinic. As expected, the feasibility of such treatment in developing countries seems to be much lesser. Furthermore, the use of combined modality treatment may increase the burden on available supportive care facilities in a resource-limited population. One measure for ensuring this is to audit respective practices as they give valuable insights and guidance into practice. In this audit, we tried to look outcomes and feasibility of chemo-radiation strategies in locally advanced NSCLC. The development of tolerable but still curative treatments for individuals that who cannot tolerate concurrent therapy should be a priority in view of the large number of patients that fall in this category. Our audit showed that sequential treatment fared well if not worse and should remain a viable option for those who cannot tolerate concurrent CTRT. As we move toward personalized therapy or individualized treatment, partial responders can be considered for modest dose escalation of radiotherapy so as to achieve CR leading to better outcomes.
| » Conclusion|| |
In this audit of resource-limited population with locally advanced NSCLC, combination strategies of radiotherapy and chemotherapy are a feasible approach. Outcomes in terms of both disease-free and OS are comparable to the developed countries. Grade III toxicity was <5% and there were no Grade IV toxicity with acceptable mortality. CR to treatment is an important predictive factor for both progression-free survival and OS.
| » Acknowledgments|| |
We acknowledge the help of Mr Jitendra Arora and Sr. Rupali U Badhe.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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